Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non- BRCA1/2-Mutant Cancers

Cancer Discov. 2020 Oct;10(10):1528-1543. doi: 10.1158/2159-8290.CD-20-0163. Epub 2020 Jun 12.


Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K-AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K-AKT pathway alterations. SIGNIFICANCE: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic-pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K-AKT pathway alterations.This article is highlighted in the In This Issue feature, p. 1426.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • BRCA1 Protein / metabolism*
  • BRCA2 Protein / metabolism*
  • Female
  • Humans
  • Middle Aged
  • Phthalazines / pharmacology
  • Phthalazines / therapeutic use*
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Pyrroles / pharmacology
  • Pyrroles / therapeutic use*


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Pyrimidines
  • Pyrroles
  • capivasertib
  • olaparib